tbuckley/cabot-search huggingface dataset:
Phase II clinical study of tislelizumab combined with nab-paclitaxel (TRUCE-01) for muscle-invasive urothelial bladder carcinoma: Bladder preservation subgroup analysis.
Authors: Yuanjie Niu, Hailong Hu, HaiTao Wang, Dawei Tian, Gangjian Zhao, Chong Shen, Zhouliang Wu, La Da, Xuejian Zhan, Shiwang Huang
Journal: Journal of Clinical Oncology (2022)

4589 Background: The current strategy for bladder preservation is focused on trimodality treatment, including complete transurethral resection of bladder tumor (cTURBT), with concurrent chemotherapy and radiotherapy. Chemotherapy is usually a cisplatin-based regimen. However, many pts cannot tolerate cisplatin-based chemotherapy and radiation therapy. It fails to meet clinical needs. Meanwhile, the efficacy and safety of checkpoint inhibitors (ICIs) have now been demonstrated. We conduct a study to evaluate ICIs in combination with second-line chemotherapy agents for patients with MIBC. Methods: TRUCE-01 is a phase II trial (NCT04730219) of tislelizumab combined with nab-paclitaxel before cTURBT or radical cystectomy. Pts with pure or mixed urothelial bladder cancer (T2-4a Nx M0) received tislelizumab 200mg on days 1 plus paclitaxel 200mg on days 2 every 3 weeks (Q3W) x 3 cycles followed by cTURBT or radical cystectomy. Imaging evaluation is usually done before and after the drug administration using the same tests to assess the efficacy. Pts who choose to preserve bladder usually continue their medication after cTURBT. This abstract focuses on patients with bladder preservation. Results: Between July 2020 and November 2021, 47 pts completed at least 2 cycles of treatment, 22 (47%) pts received cTURBT, 16 (34%) pts received radical cystectomy and 9 (19%) pts refuse surgery. As for radiological response, 22 achieved complete response (CR), 16 achieved partial response (PR). In the bladder-preserving subgroup, 13 CR pts and 9 PR pts selected cTURBT, pathology showed 17 pT0, 1 pTa, 3 pT1 and 1 pTis. The median medication cycle is 9 (6-11). There were 3 pts experienced grade 3-4 adverse events (CTCAE), a grade 3 rash, a grade 3 gastric perforation and a grade 4 acute renal failure. In addition, The most common grade 1-2 adverse events include alopecia (86%), fatigue (77%), rash (41%), appetite decreases (41%), hyperglycemia (36%), fever (18%), and creatinine increased (14%). Median follow-up 357 (438-291) days with 3 recurrences and 1 death. The 1-year recurrence-free survival rate was 82%. Conclusions: The early efficacy data further support the role of tislelizumab combined with paclitaxel in bladder preservation setting with an acceptable adverse events. Patients with imaging CR or PR after neoadjuvant therapy are preferred for bladder preservation. Enrollment is ongoing. Clinical trial information: NCT04730219.
Drug-free biodegradable nanoparticles alleviate myeloid cell-induced immunosuppression and inhibit metastasis.
Authors: Jeffrey Ma, Ravi Raghani, Yining Zhang, Sophia Orbach, Tushar Murthy, Joseph Podojil, Adam Elhofy, Lonnie Shea
Journal: Journal of Clinical Oncology (2022)

e14555 Background: Metastasis is responsible for most cancer-related deaths and depends on the formation of a metastatic niche at distal sites. The metastatic niche consists primarily of immunosuppressive myeloid cells, such as neutrophils and monocytes. These cells are recruited to distal sites in response to cancer-induced immune dysregulation and promote the recruitment and survival of disseminated tumor cells. We have employed drug-free poly(lactide-co-glycolide) (PLGA) nanoparticles, ONP-302, to modulate myeloid cell phenotypes and trafficking to disrupt the formation of the metastatic niche. The anti-metastatic efficacy of ONP-302 nanoparticles was evaluated in a translationally relevant mouse model of orthotopic triple-negative breast cancer. Methods: ONP-302 nanoparticles were evaluated in the syngeneic 4T1 model of triple-negative breast cancer in female BALB/c or RAG1KO BALB/c mice. ONP-302 nanoparticles intravenously injected into tumor-bearing mice every 3 days starting 1 day after tumor inoculation. Lungs were extracted 14 and 21 days after inoculation for analysis by single cell RNA sequencing and quantification of metastases by luminescent imaging, respectively. In resection studies, primary tumors were resected 11 days after inoculation and tissues were extracted 42 days after resection for quantification of metastases. Results: ONP-302 nanoparticles significantly reduced primary tumor growth and completely inhibited the formation of lung metastases. ONP-302 was also effective at suppressing metastasis when applied following surgical resection. In mice which received ONP-302 after surgical resection, lung metastases were undetectable up to 42 days after resection, while 44% of control mice developed metastases. These findings suggest that ONP-302 targets both primary tumor growth and metastatic colonization. Single cell RNA sequencing was employed to analyze ONP-302 modulation of the lung metastatic niche. The lungs of ONP-302 treated mice had lower neutrophil infiltration and a higher proportion of monocytes and dendritic cells compared to control mice. Gene expression pathways associated with inflammatory interferon and tumor necrosis factor responses were upregulated in neutrophils, monocytes, and dendritic cells from ONP-302 treated mice. The upregulation of these pathways suggests that ONP-302 treatment prevents the formation of an immunosuppressive niche and promotes anti-tumor cytotoxicity. Adaptive immunity was essential for ONP-302 efficacy, as T and B cell deficient RAG1KO mice demonstrated complete loss of ONP-302 efficacy both in slowing primary tumor growth and preventing metastasis. Conclusions: Our findings demonstrate that our drug-free PLG nanoparticles, ONP-302, impede cancer metastasis as a monotherapy by inhibiting the accumulation of immunosuppressive myeloid cells.
Immunological microenvironment in colon cancer patients with different phenotypes of cancer stem cells.
Authors: Elena Yu Zlatnik, Inna A. Novikova, Elena P. Ulianova, Elena S. Bondarenko, Yuriy A. Gevorkyan, Natalya V. Soldatkina, Dmitriy S. Petrov, Vladimir E. Kolesnikov, Dmitriy A. Savchenko, Roman E. Tolmakh, Andrey V. Dashkov, Oksana V. Katelnitskaya, Sergei A. Ilchenko, Elena A. Dzhenkova, Aleksandr V. Snezhko, Evgeniy N. Kolesnikov, Aleksandr V. Shaposhnikov, Oleg I. Kit, Aleksey Yu. Maksimov
Journal: Journal of Clinical Oncology (2022)

e15503 Background: The purpose of this study was to analyze the effect of the CD44+ and CD133+ co-expression in cancer stem cells (CSCs) on lymphocytic microenvironment of colon cancer (CC). Methods: 200 CC patients received surgery as the first stage of treatment. The percentage of CSCs with the expression of CD44+ and/or CD133+ markers was studied in the tumor homogenates by flow cytometry, as well as some indicators of local immunity (CD3+, CD4+, CD8+, T regs (CD4+CD25+CD127dim), CD19+, PD-1, PD-L1, Th0, Tm, CD16/56+ and immunophenotypic characteristics of tumor cells (PD-L1, MHC-ABC). Results: Gradation depending on the absence or presence of co-expression of CSC markers on tumor cells allowed identification of 11 statistically significant differences out of 17 studied parameters of tumor cells and their lymphocytic microenvironment. Co-expression of CSC markers was accompanied by higher percentage of T regs (7.3±0.4 versus 5.3±0.5%), together with lower levels of CD4+ cells. At the same time, a higher content of the total number of T-lymphocytes was noted due to CD8+ with an increase in the percentage of memory T cells and a decline in naive T lymphocytes within this subpopulation. In addition, the co-expression of CSC markers was accompanied by a lower content of PD-L1 (34.3±3.0 vs. 42.9±2.5%) on lymphocytes and its higher content on tumor cells (10.6±1.5 vs. 4.1±0.8%), while the PD-1 expression on lymphocytes was higher (38.4±3.7 versus 22.3±2.9%). The presence of CD44+CD133+ CSCs was also accompanied by lower percentage of tumor cells expressing MHC class I (60.4±4.9 vs. 79.3±7.6%), which characterized the inhibition of recognition processes, and increased levels of CD8+, perhaps, should be considered as compensatory. Conclusions: The lymphocytic microenvironment of CC in the presence of CSCs with the CD44+CD133+ immunophenotype seems to be more immunosuppressive, according to the increase in the local content of T regs and the decrease in MHC-ABC expression. Higher expression of PD-L1 on tumor cells and PD-1 on lymphocytes allows activation of the PD-1/PD-L1 interaction, which enhances the immunosuppressive and growth-stimulating properties of the tumor microenvironment, but at the same time, makes tumor cells adequate targets for immunotherapy with immune checkpoint inhibitors.
Association of DNA damage repair (DDR) mutations (mts) and clinical outcomes in CALGB 90601 (Alliance).
Authors: Gopa Iyer, Susan Halabi, Bin Luo, Jonathan E. Rosenberg, Woonyoung Choi, Hikmat A. Al-Ahmadie, Jack Mountain, Ashley Marie Regazzi, Megan Fong, Kent William Mouw, Eliezer Mendel Van Allen, David James McConkey, Yujia Wen, Linda McCart, Karla V. Ballman, Himisha Beltran, Michael J. Morris
Journal: Journal of Clinical Oncology (2022)

4521 Background: Platinum-based chemotherapy is the standard 1st-line therapy for metastatic urothelial cancer (mUC). C90601 was a randomized phase III trial testing gemcitabine and cisplatin (GC) with bevacizumab (B) or placebo (P) in patients (pts) with untreated mUC. Median overall survival (OS) for GCB vs GCP was 14.5 months (mo) vs 14.3 mo (p=0.14) and median progression-free survival (PFS) was 8 vs 6.7 mo, respectively. DDR mts have been implicated in response and survival in mUC and were investigated in this negative trial. Methods: C90601 enrolled 506 pts randomized 1:1 to GCB or GCP from 7/15/09-12/2/14, with stratification for prior chemotherapy and visceral metastases. Consenting pts submitted archival FFPE tumor specimens and blood for matched germline (g)DNA. Tumor and gDNA were sequenced by MSK-IMPACT, a 468-gene exon capture assay, to detect mts in select DDR genes. The proportional hazards model was used to correlate mts in the DNA helicase ERCC2 (pre-specified hypothesis) and additional DDR gene panels being explored in prospective trials in muscle-invasive disease with OS and PFS, adjusting for tumor mt burden and stratification factors. Mts were categorized as deleterious (del) or non-del using pre-defined published criteria. Results: 208 pts underwent DNA sequencing. Clinical features and PFS/OS were comparable to the 506-pt cohort. Median sequencing coverage was 497X. Median mutation count was 13.2 and 8.8 for DDR mt and wild-type tumors, respectively. A non-significant improvement in OS and PFS was seen in pts with ERCC2 mts (HR 0.70), but the 5.3% frequency of ERCC2 mts was lower than in historical series. Neither del mts (table) nor any mts in DDR genes were associated with PFS/OS. Conclusions: DDR mts were not associated with improved outcomes in C90601. The reliance on archival specimens, lower-than-expected ERCC2 mt frequency, small sample sizes, and tumor genomic heterogeneity may have influenced the predictive capacity of DDR mts in this cohort. Similar analyses are underway in pts who received neoadjuvant chemotherapy prior to cystectomy from completed prospective trials. Support: U10CA180821, U10CA180882, Genentech.[Table: see text]
Final data from the phase 2a single-arm trial of SurVaxM for newly diagnosed glioblastoma.
Authors: Michael J Ciesielski, Manmeet Singh Ahluwalia, David A. Reardon, Ajay P. Abad, William T. Curry, Eric T. Wong, David M. Peereboom, Sheila A. Figel, Alan Hutson, Adrienne Groman, Henry G. Withers, Song Liu, Ahmed Belal, Jing-Xin Qiu, Kathleen Mogensen, Cathy Schilero, Danielle M. Casucci, Laszlo Mechtler, Robert Alan Fenstermaker
Journal: Journal of Clinical Oncology (2022)

2037 Background: Newly diagnosed glioblastoma (nGBM) routinely treated with surgery, radiation, and temozolomide (TMZ), still result in early progression and near-universal lethality within 5 years. Tumor associated “survivin” is expressed in &gt;95% of nGBM and targetable by SurVaxM immunotherapy. Results from the recently completed multi-center phase 2a trial of SurVaxM in nGBM are presented. Methods: nGBM patients (pts) were enrolled at 5 trial sites. Eligibility criteria included: age ≥ 18, Karnofsky performance status ≥70, IHC confirmation of survivin expression, expression of HLA-A*02, A*03, A*11 or A*24 MHC-I alleles and residual contrast enhancement of ≤1 cm 3 by MRI within 72h post-resection. Pts received standard TMZ chemoradiation followed by initiation of 4 priming doses of SurVaxM (500 mcg in emulsion with Montanide ISA 51, every 2 weeks) with 100 mcg sargramostim. Maintenance doses of SurVaxM-Montanide plus sargramostim were thereafter administered every 12 weeks. Adjuvant TMZ was administered for at least 6 cycles, after at least the first dose of SurVaxM and beginning no sooner than 28 days after completion of chemoradiation. Pts were monitored by MRI every 8 weeks, and progression was assessed using modified RANO criteria. The primary endpoint was 70% progression free survival (PFS) at 6 mos. Primary analyses of median PFS (mPFS) and median overall survival (OS) were measured from first immunization. Safety, tolerability, and immune responsiveness were also determined. Results: 63 pts with nGBM were enrolled, comprised of 38 males and 25 females with a median age of 60 years. The cohort was consistent with the 4 commonly observed primary molecular GBM subtypes (classical, mesenchymal, neural and proneural). SurVaxM was well tolerated, with no serious adverse events. A strong positive correlation, accounting for censoring, was observed between PFS and OS of all pts (r = 0.79; 95% CI (0.66,0.87)). SurVaxM was immunogenic and produced survivin-specific CD8+ T-cells and antibody (IgG) titers in both methylated and unmethylated MGMT pts and both groups showed clinical benefit. Conclusions: SurVaxM appeared to be safe and well-tolerated in pts with nGBM. SurVaxM was effective at stimulating survivin-specific immune responses and the primary endpoint was met. SurVaxM represents a promising therapy for nGBM, including for those pts with unmethylated MGMT genes. For pts treated with SurVaxM, PFS may be an acceptable surrogate for OS. Clinical trial information: NCT02455557. [Table: see text]
Identification of molecular feature in tumor immune microenvironment of bladder cancer patients.
Authors: Ming Cao, Wei Xue, Jiali Zhang
Journal: Journal of Clinical Oncology (2022)

e16500 Background: Bladder cancer (BC) is the most common malignant tumor of the urinary system, with various heterogeneity. Immunotherapy has become one of the hot areas of cancer research. Tumor immune microenvironment is closely related to prognosis and immunotherapy effect. Therefore, Immune cell infiltration analysis is necessary for the prognosis and treatment of BC. Methods: In this study, we analyzed IMvigor210 dataset, which included complete expression data and detailed clinical information from a cohort associated with Bladder Urothelial Carcinoma (BLCA) immunotherapy. The dataset was divided into two groups based on tumor remission after immunotherapy, including 68 remission samples and 230 stable samples. The CIBERSORT program package was used for immune invasion analysis to compute the relative proportion of immune cells in the tumor tissue from tissue gene expression profiles. Results: Significant results of differentially immune cells proportion were obtained in 126 BC patients by CIBERSORT analysis ( p&lt; 0.05). Compared with the stable group, the number of resting memory CD4 + T cells decreased and the number of CD8 + T cells increased in the remission group. The relative proportion of immune cells in tumor microenvironment has certain influence on the occurrence and development of tumor. Conclusions: Memory CD4 + T cells in the resting state did not promote the activation and proliferation of CD8 + T cells, whereas resting memory CD4 + T cells were associated with poor outcome. The increased level of CD8 + T cells in tumor microenvironment was associated with the anti-tumor effect and improved prognosis of various cancers. The results indicate that resting memory CD4 + T cells and CD8 + T cells may be the target of immunotherapy.
Urinary potassium and association with methotrexate (MTX) elimination delay in patients with primary central nervous system lymphoma (PCNSL).
Authors: Vincent Harlay, Celine Boucard, Gregorio Petrirena, Maryline Barrie, Chantal Campello, Didier Autran, Etienne Gouton, Olivier L. Chinot, Emeline Tabouret
Journal: Journal of Clinical Oncology (2022)

e14045 Background: First-line treatment of PCNSL consists in a polychemotherapy based on high-dose MTX with hyperhydratation until MTX elimination. Renal toxicity remains frequent with pejorative impact on renal function and patient survival. Our objective was to determine urinary predictive factors of MTX elimination delay. Methods: Patients with PCNSL followed in our institution were prospectively recruited from December 2020 to May 2021. Daily serum and urinary creatinine and ionogram were collected from the day before MTX administration until elimination. Patients characteristics, biological data and MTX concentration were recorded. Normal elimination time was defined by MTX ≤ 0.05 at 72 hours. Results: We collected data from 64 MTX cycles corresponding to 20 patients. Median age was 71 years (range, 33 - 86) and median Karnofsky Performance Status (KPS) was 70. Forty-four percent of cycles were full dose (3500 mg/m 2 ). Median urinary osmolarities one day before, the day and 24 hours after MTX administration were 325 mOsm (range, 62 - 542), 316 mOsm (range, 58 - 671) and 291 mOsm (range, 56 - 554), respectively. Median time for MTX elimination was 94.7 hours (range, 47 - 205). Only one patient needed to receive MTX antidote (glucarpidase). The factors significantly associated with MTX elimination time were age (p &lt; 0.001), KPS (p &lt; 0.001) and urinary K+ concentration at 24 hours post MTX administration (u-K+) (p = 0.008). Using ROC curve analyses, we determine optimal cutoffs for age (80 years, p &lt; 0.001, AUC = 0.825), KPS (70, p &lt; 0.001, AUC = 0.808) and u-K+ (17.2 mmol/L, p = 0.008 AUC = 0.712). This u-K+ cutoff presented with a specificity of 81% and a sensibility of 60%. Focusing on patients aged &lt; 80 years (52 cycles / 64), we confirmed that both KPS (p = 0.022) and u-K+ (p = 0.027) were significantly correlated with MTX elimination time by multivariate analysis. Then, we derived a 3-factors score including 5 subgroups: 1) aged ≥ 80 (N = 12); 2) age &lt; 80, KPS &lt; 70 and high u-K+ (N = 11); 3) age &lt; 80, KPS &lt; 70 and low u-K+ (N = 6); 4) age &lt; 80, KPS ≥ 70 and high u-K+ (N = 8); 5) age &lt; 80, KPS≥70 and low u-K+ (N = 21). The median times for MTX elimination were 112, 96, 95, 82 and 72 hours respectively. The normal elimination rates in each subgroup were 17%, 0%, 17%, 37% and 71% respectively. Conclusions: Age, KPS and u-K+ were correlated with MTX elimination time. We derived a predictive score based on these items that could be used in routine to anticipate MTX elimination delay and to potentially prevent the risk of renal toxicity. These results need to be prospectively confirmed in a larger cohort.
Neo-adjuvant T-VEC plus nivolumab combination therapy for resectable early-stage or metastatic (IIIB-IVM1a) melanoma with injectable disease: The NIVEC trial.
Authors: Maartje W. Rohaan, Lisanne P. Zijlker, Emma H.A. Stahlie, Viola Franke, Sofie Wilgenhof, Vincent van der Noort, Alexander Christopher Jonathan Van Akkooi, John B. A. G. Haanen
Journal: Journal of Clinical Oncology (2022)

TPS9607 Background: The prognosis of patients with melanoma is significantly correlated with disease stage and has greatly improved with the introduction of the currently approved therapies. Trials investigating neo-adjuvant treatment with immune checkpoint inhibitors (ICI) have shown high pathologic response rates up to 25-80%, however, still a large group of patients derive no (durable) clinical benefit. Treatment with talimogene laherparepvec (T-VEC), a modified herpes simplex virus type-1, is approved for patients with unresectable stage IIIB-IVM1a melanoma, with high and durable response rates and a mild toxicity profile. Earlier trials have suggested that T-VEC has the capacity to heighten the immune response and to elicit an abscopal effect in melanoma when given in combination with ICI. Combination ICI and intralesional T-VEC has already been investigated in patients with unresectable stage IIIB-IV disease, however, no data is available yet on the potential benefit of this combination therapy in neo-adjuvant setting. This is the first trial investigating the efficacy and safety of neo-adjuvant treatment of T-VEC in combination with nivolumab (anti-PD-1 antibody), followed by surgical resection in patients with resectable stage IIIB-IVM1a melanoma, with the potential of high pathologic response rates and acceptable toxicity. Methods: In this single center, single arm, phase II study, a total of 24 patients ≥18 years of age and a good clinical performance score with treatment naïve, stage IIIB-IVM1a melanoma (AJCC 8 th edition) with injectable disease and resectable (sub)cutaneous satellite or in-transit metastases and/or tumor positive lymph nodes, will be included. Patients will receive four courses of T-VEC up to 4mL (first dose as seroconversion dose) and three doses of nivolumab (240mg flatdose) every two weeks, followed by surgical resection in week nine. The primary endpoint of this trial is pathologic response rate, with the aim to show a high major pathologic (near-complete or complete) response rate up to 45%. Secondary endpoints are safety according to CTCAE v5.0, the rate of delay of surgery and event free survival. Additionally, prognostic and predictive biomarker research and health-related quality of life evaluation will be performed. Enrollment started in June 2020 in the Netherlands Cancer Institute, with currently 13 of the 24 planned patients treated. Clinical trial information: NCT04330430.